Nowadays, molecule-integrated bioassay substrates with predetermined DNAs finely arrayed thereon by microarray techniques, which are generally called DNA chips or DNA microarrays (hereinafter collectively called “DNA chips”), are used in mutation analyses of genes, SNPs (single-base polymorphisms) analyses, gene expression frequency analyses, and the like, and have begun to find utility in a wide variety of fields such as drug developments, clinical diagnoses, pharmacogenomics and forensic medicine.
This DNA chip is characterized in that it permits a comprehensive analysis of intermolecular reactions such as hybridizations, because a wide variety of numerous DNA oligosaccharide chains, cDNAs (complementary DNAs) or the like are integrated on a glass substrate or silicon substrate.
An illustrative analytical procedure by a DNA chip will be described briefly. To a DNA probe immobilized on a glass substrate or silicon substrate, hybridization is performed on the substrate by subjecting mRNA, which has been extracted from cells, a tissue or the like, to PCR amplification in the presence of a fluorescence-labeled dNTP by reverse transcriptase PCR reaction or the like while integrating the fluorescence-labeled dNTP as a fluorescent probe. Fluorometry is then performed with a prescribed detector.
With a view to achieving an increase in the number of target substances to be handled and improvements in detection accuracy and detection speed in a bioassay method making use of the above-described DNA chip, substrate techniques and servo control techniques fostered in connection with optical disks can be proposed.
Described specifically, a solution with a detection substance contained therein is dropped to a predetermined position on a substrate while rotating the same, and is immobilized on the substrate. With the substrate kept rotating, a solution with a fluorescence-labeled target substance contained therein is then dropped onto the immobilized detection substance to cause the detection substance and the target substance to interact with each other, and the target substance not contributed to the interaction is washed off. With the substrate kept in rotation, excitation light is subsequently irradiated onto the interacted target substance, fluorescence emitted from the fluorescent label is detected by a detector, and an intensity of the fluorescence so detected is determined to analyze the binding strength between the detection substance and the target substance (see, for example, JP 2001-238674 A).
The above-described bioassay method making use of a substrate (hereinafter called “disk assay” for the sake of convenience in description) has a merit in that compared with the conventional one called “DNA chip”, a huge number of detection substances and target substances can be very economically arrayed on a substrate by making use of injection molding techniques, which are employed in the preparation of substrates for optical disks, and surface microprocessing techniques.
Further, it is possible to achieve an improvement in detection speed by rotating a substrate at a high speed and performing fluorometric detections with a high-sensitivity detector. There is a further merit in that, if samples of a target substance carried at a high degree of integration on a substrate as described above are repeatedly analyzed by a high-speed assay system, the results can be statistically processed to achieve an improvement in detection accuracy.
In the above-described disk assay, however, a sample solution is dropped downwardly from a point above a substrate, which is held in a horizontal position, onto predetermined detecting sections (spot regions). Accordingly, a dropper (for example, an inkjet printing apparatus) is arranged above the substrate. If a construction is adopted such that a detection unit is arranged above the substrate for the detection of the intensity of fluorescence emitted from each fluorescence-labeled target substance, a problem therefore arises in the allocation of spaces for the dropper group and the detection unit, leading to a technical problem that the arrangement of the dropper group becomes complex. Under the current circumstance that the move toward more complex droppers equipped with a greater number of nozzles is expected to advance further, it is crucial to solve the above-described technical problem.
In a disk assay, it is important to assure fail-free operations of a focusing servo control system, which serves to maintain constant the distance between the substrate and a condenser lens, and a tracking servo control system, which serves to cause a fluorescence condenser lens to track detection substances and target substances arrayed on the substrate, so that effects of dynamic disturbances caused by eccentricity and warpage of the substrate can be reduced.
Servo control information (a servo error signal), which is required to operate these servo control systems, are obtained by irradiating a laser beam onto a surface of the disk through the condenser lens and optically and electrically processing the laser beam reflected back to the condenser lens. On the surface of the substrate, however, the detection substance and the target substance are unevenly present from the optical viewpoint. Therefore, the reflected laser beam returned as a result of upward reflection of the laser beam irradiated from a side above the substrate has been subjected to scattering. As a consequence, the servo error signal includes a large noise, developing a technical problem that the operations of the servo control systems are rendered unstable.
A primary object of the present invention is, therefore, to solve the problem in allocating spaces above the detection unit and specifically, to provide a bioassay system which can stabilize servo-controlled operations with respect to a substrate.